ABSTRACT A large proportion of people worldwide, especially in developed countries, have increased serum cholesterol levels. In 2012, the CDC estimated that 95 million of adults in U.S. and up to 7% of children (6-19 years of age) have high total cholesterol levels. Further, a majority of adults in the U.S. (>95%) and a significant proportion of adolescents carry gammaherpesviruses, cancer-associated pathogens that establish life-long infection. While it is clear that hypercholesterolemia is frequently accompanied by increased inflammation and drives cardiovascular disease, it is not clear whether any relationship exists between elevated cholesterol levels and gammaherpesvirus infection, in spite of the fact that such a relationship could influence the development of both cardiovascular disease and viral tumorigenesis. Based on our preliminary data, the proposed studies test the following working model. Genetic variants, diet, and gammaherpesvirus infection all contribute to elevated circulating levels of lipoprotein-associated cholesterol (HDL-C and LDL-C; S.A.2). We hypothesize that elevated high density lipoprotein-cholesterol (HDL-C) has minimal effect on chronic gammaherpesvirus infection and disease (S.A.1 and 3). In contrast, we propose that elevated LDL-C levels lead to enhanced differentiation of T follicular helper cells (TFH), boosting the germinal center response and expansion of viral latent reservoir (S.A.1). Further, increased LDL-C is hypothesized to increase lytic gammaherpesvirus replication directly, via effects on infected cells, and indirectly, via attenuation of antiviral CD8 T cell response (S.A.1 and 2). Finally, the increased viral replication is proposed to facilitate the development of atherosclerosis in a host with elevated LDL-C levels (S.A.3). Successful completion of the proposed experiments will, for the first time, define a physiologically relevant relationship between ubiquitous chronic gammaherpesvirus infection and hypercholesterolemia, a relationship that is likely to occur, yet remains unexplored, in a significant proportion of U.S. population and modify the development of cardiovascular disease and virus-driven cancer. The feasibility of these proposed multidisciplinary and collaborative studies is supported by the synergism between the distinct, yet complementary expertise of the two PIs in cholesterol homeostasis and gammaherpesvirus infection.